Azaindole derivatives as jak3 inhibitors

ABSTRACT

The present disclosure provides compounds that are JAK3 inhibitors and therefore useful for the treatment of diseases treatable by inhibition of JAK3 such as cancer and inflammatory diseases. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

The present disclosure provides compounds that are JAK3 inhibitors andtherefore useful for the treatment of diseases treatable by inhibitionof JAK3 such as cancer and inflammatory diseases. Also provided arepharmaceutical compositions containing such compounds and processes forpreparing such compounds.

JAK3 is a cytoplasmic tyrosine kinase that functions downstream of thecommon gamma chain receptor subunit for cytokine signaling. It iscrucial for signal transduction in response to stimulation by IL-2,IL-4, IL-5, IL-7, IL-9, and IL-21 (see Shuai K and Liu B. Regulation ofJAK-STAT signaling in the immune system. Nat Rev Immunol. 3:900-11. 2003and O'Shea J. J, et al. A new modality for immunosuppression: targetingthe JAK/STAT pathway. Nat Rev Drug Discov. 3:555-64. 2004). Theexpression of JAK3 is restricted to mainly lymphoid and myeloid cells incontrast to the other Jak family members, which are more ubiquitouslyexpressed (see Johnston J A, et al. Phosphorylation and activation ofthe Jak-3 Janus kinase in response to interleukin-2. Nature. 370:151-3.1994). This makes JAK3 an attractive target for immunosuppression. JAK3null humans have a severe combined immunodeficiency disease (SCID).These individuals display lack of circulating T and NK cells with normalnumbers of B cells (see Pesu M, et al. JAK3, severe combinedimmunodeficiency, and a new class of immunosuppressive drugs. ImmunolRev. 203:127-42. 2005). In mice, JAK3 deficiency results in not only Tand NK cell depletion, but B cells as well (see Pesu M, et al. JAK3,severe combined immunodeficiency, and a new class of immunosuppressivedrugs. Immunol Rev. 203:127-42. 2005). CP-690-550, a pan Jak inhibitor,blocks the mixed lymphocyte reaction (MLR) (see Kudlacz E, et al. Thenovel JAK-3 inhibitor CP-690550 is a potent immunosuppressive agent invarious murine models. Am J Transplant. 4:51-7. 2004), the delayed-typehypersensitivity response (DTH) (see Kudlacz E, et al. The novel JAK-3inhibitor CP-690,550 is a potent immunosuppressive agent in variousmurine models. Am J Transplant. 4:51-7. 2004), as well as thecollagen-induced arthritis model (see Milici A J, et al. Cartilagepreservation by inhibition of Janus kinase 3 in two rodent models ofrheumatoid arthritis. Arthritis Res Ther. 10:R14 1-9. 2008). Other Jakfamily members include Jak2, which is involved in hematopoietic growthfactor signaling, and Jak1 and Tyk2 which in combination with Jak2 areimportant for interferon signaling and contribute to host resistance(see Shuai K and Liu B. Regulation of JAK-STAT signaling in the immunesystem. Nat Rev Immunol. 3:900-11. 2003).

Compounds that target the JAK pathway are in clinical development, butnone is selective for a single JAK family member. However, these studiesprovide clinical validation of the JAK pathway in rheumatoid arthritis(see Krenmer J, et al. The oral Jak inhibitor CP-690,550 in combinationwith methotrexate is efficacious, safe and well tolerated in patientswith active rheumatoid arthritis with an inadequate response tomethotrexate alone. Arthritis & Rheum. 58:4030a. 2008). Improvements indisease activity are observed as early as 1 week after initiation oftreatment with significant improvements in ACR20, ACR50 and ACR70 asearly as 4 weeks. Other clinical applications for JAK3 inhibitioninclude kidney transplantation, Crohn's disease, psoriasis, andJAK3-dependent hematopoietic malignancies (see Ghoreschi K, et al.,Janus kinases in immune cell signaling. Immunol Rev. 228:273-87. 2009).A short-term study with CP-690,550 on psoriasis patients demonstratedefficacy, suggesting possible utility in this indication (see Boy M G,et al. Double-blind, placebo-controlled, dose-escalation study toevaluate the pharmacologic effect of CP-690,550 in patients withpsoriasis. J Invest Dermatol. 129:2299-302. 2009).

In addition, mutations resulting in persistent activation of JAK/STATsignaling have been described and attributed to the pathogenesis ofvarious leukemias and lymphomas including T-cell acute lymphoblasticleukemia (T-ALL; Bains, T. et al. Newly described activating JAK3mutations in T-cell acute lymphoblastic leukemia. Leukemia 26:2144-2146. 2012; Elliott, N. E. et al FERM domain mutations induce gainof function in JAK3 in adult T-cell leukemia/lymphoma. Blood 118:3911-3921. 2011), and natural killer cell-T cell lymphoma (NK-TCL;Bouchekioua, A. et al., JAK3 deregulation by activating mutationsconfers invasive growth advantage in extranodal nasal-type naturalkiller cell lymphoma. Leukemia May 21.2013; Koo, G. C. et al. Januskinase 3-activating mutations identified in natural killer/T-celllymphoma. Cancer Discovery 2: 591-597, 2013). Studies in BaF3 cells haveshown that these mutations can be transforming (Malinge, S. et al.Activating mutations in human acute megakaryoblastic leukemia. Blood112: 4220-4226. 2008; Walters, D. K. et al Activating alleles of JAK3 inacute megakaryoblastic leukemia. Cancer Cell 10: 65-75, 2006). TheJAK-STAT pathway may be also be activated in other T-cell lymphomas eventhough there are no detectable mutations in JAK3, resulting from loss ofSHP1, SOCS3, NPM-ALK fusion or other unknown causes. For example,constitutive STATS activation is a characteristic feature of malignantcell lines derived from the skin and blood of CTCL patients (Fantin, V Ret al. Constitutive activation of signal transducers and activators oftranscription predicts vorinostat resistance in cutaneous T-celllymphoma. Cancer Res. 68:3785-3794. 2008). The pan-JAK inhibitorCP-690,550 inhibits proliferation of JAK3 mutated NK-TCL cells (Koo, G.C. et al. Janus kinase 3-activating mutations identified in naturalkiller/T-cell lymphoma. Cancer Discovery 2: 591-597, 2013).

Accordingly, there is a need for compounds that inhibit JAK3 therebyproviding treatment for diseases such as autoimmune diseases,inflammatory diseases, and cancer.

SUMMARY

In one aspect, provided are a compound of Formula (I):

wherein:

Z¹ is N or CR⁶ where R⁶ is hydrogen, alkyl, halo, haloalkyl, haloalkoxy,or cyano;

R¹ is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, cyano, orcycloalkyl;

R² is hydrogen, alkyl, cycloalkyl, halo, cyano, acyl, aminocarbonyl,phenyl or heteroaryl wherein phenyl and heteroaryl is optionallysubstituted with one, two or three substituents independently selectedfrom alkyl, alkoxy, halo, haloalkyl, or haloalkoxy;

Ar is phenyl or 5- or 6-membered heteroaryl;

R³ is -(alkylene)_(n)—Y—CH═CHR^(c) [where n is 0 or 1, Y is —NR^(a)CO—,—NR^(a)SO₂—, —CO— or —SO₂— (where R^(a) is hydrogen or alkyl) and R^(c)is hydrogen, alkyl, NH₂alkyl, alkylaminoalkyl, or dialkylaminoalkyl] or-(alkylene)_(n)-Y—CH≡CR^(d) where R^(d) is hydrogen or alkyl;

R⁴ is hydrogen, alkyl, alkoxy, hydroxyl, halo, haloalkyl, haloalkoxy,hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkyloxy,heterocyclylalkyl optionally substituted with one or two substitutentsindependently selected from alkyl, halo, hydroxyalkyl, or alkoxyalkyl,heterocyclyloxy optionally substituted with one or two substitutentsindependently selected from alkyl, halo, hydroxyalkyl, or alkoxyalkyl,heterocyclylalkyloxy optionally substituted with one or twosubstitutents independently selected from alkyl, halo, hydroxyalkyl, oralkoxyalkyl, aminoalkyl, or aminoalkoxy; and

R⁵ is hydrogen, alkyl, alkoxy, hydroxyl, halo, haloalkyl, haloalkoxy, orcyano; and/or a pharmaceutically acceptable salt thereof.

In one embodiment, the compounds of Formula (I) forms irreversiblecovalent bond with cysteine 909, (UniprotKB Sequence ID P52333) of JAK3.

In a second aspect, provided is a pharmaceutical composition comprisinga compound of Formula (I) (or any of the embodiments thereof describedherein), and/or a pharmaceutically acceptable salt thereof; and apharmaceutically acceptable excipient.

In a third aspect, provided is a method of treating a disease treatableby inhibition of JAK3, in a patient which method comprises administeringto the patient in need thereof, a pharmaceutical composition comprisinga compound of Formula (I) (or any of the embodiments thereof describedherein) or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable excipient in an amount effective to achievethe treatment (therapeutic amount). In one embodiment of the thirdaspect, the patient is in recognized need of such treatment.

In one embodiment of this aspect, the patient in need or recognized needis suffering from an autoimmune disease, e.g., inflammatory boweldisease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis,osteoarthritis, Still's disease, juvenile arthritis, diabetes,myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves'disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barresyndrome, acute disseminated encephalomyelitis, Addison's disease,opsoclonus-myoclonus syndrome, ankylosing spondylitisis,antiphospholipid antibody syndrome, aplastic anemia, autoimmunehepatitis, coeliac disease, Goodpasture's syndrome, idiopathicthrombocytopenic purpura, optic neuritis, scleroderma, primary biliarycirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis,warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis,alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia,endometriosis, interstitial cystitis, neuromyotonia, scleroderma, orvulvodynia. In one embodiment of this aspect, the disease is rheumatoidarthritis. In another embodiment of this aspect, the autoimmune diseaseis lupus. In yet another embodiment of this aspect the autoimmunedisease is psoriasis or transplant. In another embodiment of thisaspect, the patient in need or recognized need is suffering from aheteroimmune condition or disease, e.g., graft versus host disease,transplantation, transfusion, anaphylaxis, allergy, type Ihypersensitivity, allergic conjunctivitis, allergic rhinitis, or atopicdermatitis.

In another embodiment of this aspect, the patient in need or recognizedneed is suffering from an inflammatory disease, e.g., asthma,appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis,cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis,cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis,endocarditis, endometritis, enteritis, enterocolitis, epicondylitis,epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis,hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis,myelitis myocarditis, myositis, nephritis, oophoritis, orchitis,osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis,pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis,prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis,vasculitis, or vulvitis.

In another embodiment of this aspect, the patient is in need orrecognized need is suffering from inflammatory skin disease whichincludes, by way of example, dermatitis, contact dermatitis, eczema,urticaria, rosacea, and scarring psoriatic lesions in the skin, joints,or other tissues or organs.

In yet another embodiment of this aspect, the patient in need orrecognized need is suffering from a cancer. In one embodiment the canceris T-ALL, CTCL, NK-T cell lymphoma, Sezary syndrome, and Mycosisfungiodes. In some embodiments, the compound of Formula (I) (or anyembodiments thereof described herein) and/or a pharmaceuticallyacceptable salt thereof is administered in combination with another ananti-cancer.

In a fourth aspect, provided are compounds of Formula (I) (and anyembodiments thereof described herein) and/or a pharmaceuticallyacceptable salt thereof for use as a medicament. In one embodiment, thecompounds of Formula (I) (and any embodiments thereof described herein)and/or a pharmaceutically acceptable salt thereof is for treatingautoimmune diseases, inflammatory disease, or proliferative diseasessuch as cancer.

In a fifth aspect, provided is the use of a compound of Formula (I) (andany embodiments thereof described herein) and/or a pharmaceuticallyacceptable salt thereof in the manufacture of a medicament for treatinga disease in a patient in which the activity of JAK3 contributes to thepathology and/or symptoms of the disease. In one embodiment of thisaspect, the disease is autoimmune diseases, inflammatory disease, orproliferative diseases such as cancer.

In any of the aforementioned aspects involving the treatment ofautoimmune diseases, inflammatory disease, or proliferative disorders,in one embodiment, the compounds of present disclosure are administeredin combination with at least one other anti-autoimmune,anti-inflammatory, or antiproliferative agent. In one embodiment, thedisease is cancer and the compound of Formula (I) (and any embodimentsthereof described herein) is administered in combination with at leastone additional anticancer agent such as alemtuzumab, arsenic trioxide,asparaginase (pegylated or non-), bevacizumab, cetuximab, platinum-basedcompounds such as cisplatin, cladribine,daunorubicin/doxorubicin/idarubicin, irinotecan, fludarabine,5-fluorouracil, gemtuzamab, methotrexate, paclitaxel, Taxol™,temozolomide, thioguanine, or classes of drugs including hormones (anantiestrogen, an antiandrogen, or gonadotropin releasing hormoneanalogues, interferons such as alpha interferon, nitrogen mustards suchas busulfan or melphalan or mechlorethamine, retinoids such astretinoin, topoisomerase inhibitors such as irinotecan or topotecan,tyrosine kinase inhibitors such as gefinitinib or imatinib, or agents totreat signs or symptoms induced by such therapy including allopurinol,filgrastim, granisetron/ondansetron/palonosetron, or dronabinol. Whencombination therapy is used, the agents can be administeredsimultaneously or sequentially.

DEFINITIONS

Unless otherwise stated, the following terms used in the specificationand claims are defined for the purposes of this application and have thefollowing meaning:

“Alkyl” means a linear saturated monovalent hydrocarbon radical of oneto six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to six carbon atoms, e.g., methyl, ethyl, propyl,2-propyl, butyl (including all isomeric forms), pentyl (including allisomeric forms), and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms unless otherwise stated e.g., methylene,ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene,pentylene, and the like.

“Alkylthio” means a —SR radical where R is alkyl as defined above, e.g.,methylthio, ethylthio, and the like.

“Alkylsulfonyl” means a —SO₂R radical where R is alkyl as defined above,e.g., methylsulfonyl, ethylsulfonyl, and the like.

“Amino” means a —NH₂.

“Alkylamino” means an —NHR radical where R is alkyl as defined above,e.g., methylamino, ethylamino, propylamino, or 2-propylamino, and thelike.

“Alkylaminoalkyl” means a linear monovalent hydrocarbon radical of oneto six carbon atoms or a branched monovalent hydrocarbon radical ofthree to six carbons substituted with at least one —NHR group, (in oneembodiment one —NHR group) where R is alkyl as defined above, e.g.,2-methyaminoethyl, 2-methyamino- or 3-methylaminopropyl, and the like.

“Dialkylaminoalkyl” means a linear monovalent hydrocarbon radical of oneto six carbon atoms or a branched monovalent hydrocarbon radical ofthree to six carbons substituted with at least one —NRR′ group, (in oneembodiment one —NRR′ group) where R and R′ are alkyl as defined above,e.g., 2-dimethyaminoethyl, 2-dimethyamino- or 3-dimethylaminopropyl, andthe like.

“Aminoalkyl” means a linear monovalent hydrocarbon radical of one to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbons substituted with at least one NRR′ group, (in one embodimentone NRR′ group) where R and R′ are independently hydrogen or alkyl asdefined above, e.g., 2-aminoethyl, 2-methyamino- or2-dimethylaminoethyl, and the like.

“Aminoalkyloxy” a —OR radical where R is aminoalkyl as defined above,e.g., e.g., 2-aminoethyloxy, 2-methyamino- or 2-dimethylaminoethyloxy,diethylaminopropyloxy, and the like.

“Alkoxy” means a —OR radical where R is alkyl as defined above, e.g.,methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, andthe like.

“Alkoxyalkyl” means a linear monovalent hydrocarbon radical of one tosix carbon atoms or a branched monovalent hydrocarbon radical of threeto six carbons substituted with at least one alkoxy group, (in oneembodiment one or two alkoxy groups), as defined above, e.g.,2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.

“Alkoxyalkyloxy” means a —O-alkoxyalkyl radical where alkoxyalkyl is asdefined above. Representative examples include, but are not limited to,methoxymethyloxy, 2-methoxyethyloxy, 2-methoxypropyloxy,3-methoxypropyloxy, and the like.

“Alkylcarbonyl” means an —COR radical where R is alkyl as defined above.Representative examples include, but are not limited to, methylcarbonyl,and the like.

“Alkoxycarbonyl” means a —C(O)OR radical where R is alkyl as definedabove, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.

“Aminocarbonyl” means a —CONR″R′ radical where R″ is independentlyhydrogen, alkyl, or substituted alkyl, each as defined herein and R′ ishydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, or substituted alkyl,each as defined herein and wherein the cycloalkyl, aryl, heteroaryl orheterocyclyl ring either alone or part of another group such as aralkyl,is optionally substituted with one, two, or three substituentsindependently selected from alkyl, halo, haloalkyl, haloalkoxy, alkoxy,cyano, carboxy, hydroxyl, —CONR″R′ (where R″ and R′ are hydrogen oralkyl) alkylcarbonyl, alkylthio, or alkylsulfonyl, e.g., —CONH₂,methylaminocarbonyl, 2-dimethylaminocarbonyl, and the like.

“Acyl” means a —COR radical where R is alkyl, substituted alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, or heterocyclylalkyl, each as definedherein and wherein the cycloalkyl, aryl, heteroaryl or heterocyclyl ringeither alone or part of another group such as aralkyl, is optionallysubstituted with one, two, or three substituents independently selectedfrom alkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, carboxy,hydroxyl, —CONR″R′ (where R″ and R′ are hydrogen or alkyl),alkylcarbonyl, alkylthio, or alkylsulfonyl, e.g., acetyl, propionyl,benzoyl, pyridinylcarbonyl, and the like. When R″ is alkyl, the radicalis also referred to herein as alkylcarbonyl.

“Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbonradical of 6 to 10 ring atoms e.g., phenyl or naphthyl.

“Aralkyl” means a -(alkylene)-R radical where R is aryl as definedabove.

“Cycloalkyl” means a cyclic saturated monovalent hydrocarbon radical ofthree to ten carbon atoms wherein one or two carbon atoms may bereplaced by an oxo group, e.g., cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, and the like.

“Cycloalkylalkyl” means a -(alkylene)-R radical where R is cycloalkyl asdefined above; e.g., cyclopropylmethyl, cyclobutylmethyl,cyclopentylethyl, or cyclohexylmethyl, and the like.

“Carboxy” means —COOH.

“Halo” means fluoro, chloro, bromo, or iodo. In one embodiment, halo isfluoro or chloro.

“Haloalkyl” means alkyl radical as defined above, which is substitutedwith one or more halogen atoms, (in one embodiment one to five halogenatoms), such as fluorine or chlorine, including those substituted withdifferent halogens, e.g., —CH₂Cl, —CF₃, —CHF), —CH₂CF₃, —CF₂CF₃,—CF(CH₃)₂, and the like. When the alkyl is substituted with only fluoro,it is referred to in this application as fluoroalkyl.

“Haloalkoxy” means a —OR radical where R is haloalkyl as defined abovee.g., —OCF₃, —OCHF₂, and the like. When R is haloalkyl where the alkylis substituted with only fluoro, it is referred to in this applicationas fluoroalkoxy.

“Hydroxyalkyl” means a linear monovalent hydrocarbon radical of one tosix carbon atoms or a branched monovalent hydrocarbon radical of threeto six carbons substituted with one or two hydroxy groups, provided thatif two hydroxy groups are present they are not both on the same carbonatom. Representative examples include, but are not limited to,hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl. In one embodiment hydroxyalkyl is2-hydroxyethyl, 2,3-dihydroxypropyl, and1-(hydroxymethyl)-2-hydroxyethyl.

“Hydroxyalkyloxy” means a —O-hydroxyalkyl radical where hydroalkyl is asdefined above. Representative examples include, but are not limited to,hydroxymethyloxy, 2-hydroxyethyloxy, 2-hydroxypropyloxy,3-hydroxypropyloxy, 1-(hydroxymethyl)-2-methylpropyloxy,4-hydroxybutyloxy, and the like.

“Heterocyclyl” means a saturated or unsaturated monovalent monocyclicgroup of 4 to 8 ring atoms in which one or two ring atoms are heteroatomselected from N, O, or S(O)_(n), where n is an integer from 0 to 2, theremaining ring atoms being C. The heterocyclyl ring is optionally fusedto a (one) aryl or heteroaryl ring as defined herein provided the aryland heteroaryl rings are monocyclic. The heterocyclyl ring fused tomonocyclic aryl or heteroaryl ring is also referred to in thisapplication as “bicyclic heterocyclyl” ring. Additionally, one or tworing carbon atoms in the heterocyclyl ring can optionally be replaced bya —CO— group. More specifically the term heterocyclyl includes, but isnot limited to, pyrrolidino, piperidino, homopiperidino,2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino,tetrahydropyranyl, oxetanyl, thiomorpholino, and the like. When theheterocyclyl ring is unsaturated it can contain one or two ring doublebonds provided that the ring is not aromatic. When the heterocyclylgroup contains at least one nitrogen atom, it is also referred to hereinas heterocycloamino and is a subset of the heterocyclyl group. When theheterocyclyl group is a saturated ring and is not fused to aryl orheteroaryl ring as stated above, it is also referred to herein assaturated monocyclic heterocyclyl.

“Heterocyclyloxy” means a —O-heterocyclyl radical where heterocyclyl isas defined above. Representative examples include, but are not limitedto, piperidinyloxy, piperazinyloxy, tetrahydrofuranyloxy, oxetanyloxy,morpholinyloxy, and the like.

“Heterocyclylalkyl” means a -(alkylene)-R radical where R isheterocyclyl ring as defined above e.g., tetrahydrofuranylmethyl,piperazinylmethyl, morpholinylethyl, and the like.

“Heterocyclylalkyloxy” means a —O-heterocyclylalkyl radical whereheterocyclylalkyl is as defined above. Representative examples include,but are not limited to, piperidinylmethyloxy, piperazinylethyl- orpropyloxy, tetrahydrofuranylmethyloxy, morpholinylmethyl-, ethyl-, orpropyloxy, and the like.

“Heterocycloamino” means a saturated or unsaturated monovalentmonocyclic group of 4 to 8 ring atoms in which one or two ring atoms areheteroatom selected from N, O, or S(O)_(n), where n is an integer from 0to 2, the remaining ring atoms being C provided that at least one of thering atoms is N. Additionally, one or two ring carbon atoms in theheterocycloamino ring can optionally be replaced by a —CO— group. Unlessotherwise stated, the heterocyloamino ring can optionally be substitutedwith one, two, or three substituents independently selected from alkyl,hydroxyl, alkoxy, amino, alkylamino, or dialkylamino.

“Heteroaryl” means a monovalent monocyclic or bicyclic aromatic radicalof 5 to 10 ring atoms where one or more, (in one embodiment one, two, orthree), ring atoms are heteroatom selected from N, O, or S, theremaining ring atoms being carbon. Representative examples include, butare not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl,indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl,quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazolyl, tetrazolyl, and the like.

“Heteroaralkyl” means an -alkylene-R radical where R is heteroaryl asdefined above.

The present disclosure also includes the prodrugs of compounds ofFormula (I). The term prodrug is intended to represent covalently bondedcarriers, which are capable of releasing the active ingredient ofFormula (I) when the prodrug is administered to a mammalian subject.Release of the active ingredient occurs in vivo. Prodrugs can beprepared by techniques known to one skilled in the art. These techniquesgenerally modify appropriate functional groups in a given compound.These modified functional groups however regenerate original functionalgroups in vivo or by routine manipulation. Prodrugs of compounds ofFormula (I) include compounds wherein a hydroxy, amino, carboxylic, or asimilar group is modified. Examples of prodrugs include, but are notlimited to esters (e.g., acetate, formate, and benzoate derivatives),carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy or aminofunctional groups in compounds of Formula (I)), amides (e.g.,trifluoroacetylamino, acetylamino, and the like), and the like. Prodrugsof compounds of Formula (I) are also within the scope of the presentdisclosure.

The present disclosure also includes protected derivatives of compoundsof Formula (I). For example, when compounds of Formula (I) containgroups such as hydroxy, carboxy, thiol or any group containing anitrogen atom(s), these groups can be protected with a suitableprotecting groups. A comprehensive list of suitable protective groupscan be found in T. W. Greene, Protective Groups in Organic Synthesis,John Wiley & Sons, Inc. (1999), the disclosure of which is incorporatedherein by reference in its entirety. The protected derivatives ofcompounds of Formula (I) can be prepared by methods well known in theart.

The present disclosure also includes polymorphic forms (amorphous aswell as crystalline) and deuterated forms of compounds of Formula (I).

A “pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include:

acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as formic acid, acetic acid,propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolicacid, pyruvic acid, lactic acid, malonic acid, succinic acid, malicacid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, and the like; or

salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like. It is understood that thepharmaceutically acceptable salts are non-toxic. Additional informationon suitable pharmaceutically acceptable salts can be found inRemington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton, Pa., 1985, which is incorporated herein by reference.

The compounds of the present disclosure may have asymmetric centers.Compounds of the present disclosure containing an asymmetricallysubstituted atom may be isolated in optically active or racemic forms.It is well known in the art how to prepare optically active forms, suchas by resolution of materials. All chiral, diastereomeric, racemic formsare within the scope of the present disclosure, unless the specificstereochemistry or isomeric form is specifically indicated.

Certain compounds of Formula (I) can exist as tautomers and/or geometricisomers. All possible tautomers and cis and trans isomers, as individualforms and mixtures thereof are within the scope of this disclosure.Additionally, as used herein the term alkyl includes all the possibleisomeric forms of said alkyl group albeit only a few examples are setforth. Furthermore, when the cyclic groups such as aryl, heteroaryl,heterocyclyl are substituted, they include all the positional isomersalbeit only a few examples are set forth. Furthermore, all polymorphicforms and hydrates of a compound of Formula (I) are within the scope ofthis disclosure.

“Oxo” or “carbonyl” means ═(O) group.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “heterocyclyl group optionallysubstituted with an alkyl group” means that the alkyl may but need notbe present, and the description includes situations where theheterocyclyl group is substituted with an alkyl group and situationswhere the heterocyclyl group is not substituted with alkyl.

A “pharmaceutically acceptable carrier or excipient” means a carrier oran excipient that is useful in preparing a pharmaceutical compositionthat is generally safe, non-toxic and neither biologically nor otherwiseundesirable, and includes a carrier or an excipient that is acceptablefor veterinary use as well as human pharmaceutical use. “Apharmaceutically acceptable carrier/excipient” as used in thespecification and claims includes both one and more than one suchexcipient.

“Substituted alkyl” means alkyl group as defined herein which issubstituted with one, two, or three substituents independently selectedfrom hydroxyl, alkoxy, carboxy, cyano, alkoxycarbonyl, alkylthio,alkylsulfonyl, halo, haloalkoxy, —SO₂NRR′, —CONR″R′ or —NRR′ (where eachR or R″ is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl, and each R′ ishydrogen, alkyl, or cycloalkyl) or heterocyclyl (in one embodimentheterocycloamino) optionally substituted with one or two groupsindependently selected from alkyl, hydroxyl, alkoxy, alkylthio,alkylsulfonyl, halo, or —CONR″R′ (where R, R′, and R″ are independentlyhydrogen or alkyl).

“Treating” or “treatment” of a disease includes:

(1) preventing the disease, i.e. causing the clinical symptoms of thedisease not to develop in a mammal that may be exposed to or predisposedto the disease but does not yet experience or display symptoms of thedisease;

(2) inhibiting the disease, i.e., arresting or reducing the developmentof the disease or its clinical symptoms; or

(3) relieving the disease, i.e., causing regression of the disease orits clinical symptoms.

A “therapeutically effective amount” means the amount of a compound ofFormula (I) that, when administered to a patient for treating a disease,is sufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

Representative compounds of Formula (I) are shown in Compound Table Ibelow:

TABLE 1 CPD # Name 1 N-(3-(7-pivaloyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)phenyl)acrylamide 22-(3-acrylamidophenyl)-N-(tert-butyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide 3 N-(tert-butyl)-2-(3-(4-(dimethylamino)but-2-enamido)phenyl)-5H-pyrrolo[2,3-b]pyrazine-7- carboxamide or a mixture ofE and Z isomers; or a pharmaceutically acceptable salt thereof.

EMBODIMENTS Embodiment A

In one group of compounds, the compound of Formula (I) or salt thereofhas the structure (Ia):

where the variables R², R³, R⁴, and R⁵ have the same definitions asthose in Formula I.

(i) Within compounds or salt thereof in embodiment A, in one group ofcompounds or salt thereof, the compounds have structure (Ib):

where the variables R², R⁴, R⁵, R^(c), Y, and n have the samedefinitions as those in Formula I.

Embodiment B

In other embodiments of Formula (I) Ar is 5- or 6-membered heteroaryl.

Within embodiment B, in one group of compounds or salt thereof Ar ispyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl, each ring substitutedwith R³, where R³ is -(alkylene)_(n)-Y—CH═CHR^(c), on the carbon atom ofthe ring that is at the meta position to the carbon attaching theaforementioned rings to the azaindole core.

Embodiment C

The compound of Formula (I) or salt thereof as defined in the Summary,embodiments A and B, and groups contained therein, wherein R² ishydrogen, alkyl, cycloalkyl, halo, cyano, —COR (where R is alkyl,heterocyclyl, heterocyclylalkyl or substituted alkyl), or —CONR″R′(where R″ is hydrogen or alkyl and R′ is hydrogen, alkyl, heterocyclyl,heterocyclylalkyl, or substituted alkyl).

Embodiment D

The compound of Formula (I) or salt thereof as defined in the Summary,embodiments A and B, and groups contained therein, wherein R² ishydrogen, methyl, isopropyl, tert-butyl, cyclopropyl, fluoro or cyano.Within the groups in Embodiment D, in one group of compounds, R² ishydrogen, methyl, tert-butyl, cyclopropyl, fluoro or cyano.

Embodiment E

The compound of Formula (I) or salt thereof as defined in the Summary,embodiments A and B, and groups contained therein, wherein R² is acyl.Within the groups in Embodiment E, in one group of compounds R² is —CORwhere R is alkyl. Within the groups in Embodiment E, in another group ofcompounds R² is —COR where R is isopropyl, isobutyl, or tert-butyl.Within the groups in Embodiment E, in yet another group of compounds R²is —COR where R is tert-butyl.

Embodiment F

The compound of Formula (I) or salt thereof as defined in the Summary,embodiments A and B, and groups contained therein, wherein R² is —CORwhere R is cycloalkyl or heterocyclyl. Within the groups in EmbodimentF, in one group of compounds R² is —COR where R is cyclopropyl,cyclohexyl, cyclopentyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,tetrahydrothiopyranyl, or 1,1,-dioxo-tetrahydrothiopyranyl. In oneembodiment R is cyclopropyl, 3-, or 4-pyrrolidinyl, 3- or4-tetrahydropyranyl, 3- or 4-piperidinyl, 3- or 4-tetrahydrothiopyranyl,3- or 4-1,1,-dioxo-tetrahydrothiopyranyl, each of which is optionallysubstituted at the carbon attached to —CO— with alkyl. Within the groupsin Embodiment F, in another group of compounds R² is —COR where methyland the ring with a ring nitrogen atoms is optionally substituted atring nitrogen with alkylcarbonyl. Within the groups in Embodiment F, inone group of compounds R² is where acetyl. Within the groups inEmbodiment F, in one group of compounds R² is —COR where R is1-methylcyclohex-1-yl.

Embodiment G

The compound of Formula (I) or salt thereof as defined in the Summary,embodiments A and B, and groups contained therein, wherein R² is —CORwhere R is heterocyclylalkyl. Within the groups in Embodiment G, in onegroup of compounds R² is —COR where R is heterocyclyl ring ispyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, or1,1,-dioxo-tetrahydrothiopyranyl. Within the groups in Embodiment G, inanother group of compounds R² is —COCH₂heterocyclyl where theheterocyclyl ring is 3-, or 4-pyrrolidinyl, 3- or 4-tetrahydropyranyl,3- or 4-piperidinyl, 3- or 4-tetrahydrothiopyranyl, 3- or4-1,1,-dioxo-tetrahydrothiopyranyl, each ring containing nitrogen ringatom is optionally substituted at ring nitrogen with alkylcarbonyl suchas acetyl and each ring is optionally substituted at the carbon attachedto —CR₂— with alkyl, such as methyl.

Embodiment H

The compound of Formula (I) or salt thereof as defined in the Summary,embodiments A and B, and groups contained therein, wherein R² is —CORwhere R is substituted alkyl. Within the groups in Embodiment H, in onegroup of compounds R² is —COR where R is alkyl substituted with one ortwo hydroxyl, alkoxy, or amino. Within the groups in Embodiment H, inanother group of compounds R² is —COR where R is 1,3-dimethoxyprop-2-yl,—C(CH₃)₂CH₂NH₂, —CH(CH₃)CH₂OCH₃, 1,3-dihydroxyprop-2-yl, —CH(CH₃)CH₂OH,1,3-dihydroxy-2-methylprop-2-yl, —C(CH₃)(OC₂H₅)₂, —CH₂C(CH₃)₂CH₂OH,2-hydroxypropyl, 3-methoxyprop-2-yl, 2-methoxyprop-1-yl,2,3-dihydroxyprop-1-yl, 2-methoxyethyl, 3-methoxypropyl, —CH₂C(CH₃)₂OCH₃, 3-methoxybutyl, —C(CH₃)₂O CH₃, or methoxymethyl.

Embodiment I

The compound of Formula (I) or salt thereof as defined in the Summary,embodiments A and B, and groups contained therein, wherein R² isaminocarbonyl. Within the groups in Embodiment I, in one group ofcompounds R² is —CONHR′ where R′ is alkyl. Within the groups inEmbodiment I, in one group of compounds R² is —CONHR′ where R′ isisopropyl, isobutyl, or tert-butyl. Within the groups in Embodiment I,in one group of compounds R² is —NH tert-butyl. Within the groups inEmbodiment I, in one group of compounds R² is —CONHisopropyl.

Embodiment J

The compound of Formula (I) or salt thereof as defined in the Summary,embodiments A and B, and groups contained therein, wherein R² is —CONHR′where R′ is cycloalkyl or heterocyclyl. Within the groups in EmbodimentJ, in one group of compounds R² is —CONHR′ where R′ is cyclopropyl,cyclohexyl, cyclopentyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,tetrahydrothiopyranyl, or 1,1,-dioxo-tetrahydrothiopyranyl (in oneembodiment cyclopropyl, 3-, or 4-pyrrolidinyl, 3- or4-tetrahydropyranyl, 3- or 4-piperidinyl, 3- or 4-tetrahydrothiopyranyl,3- or 4-1,1,-dioxo-tetrahydrothiopyranyl), each of which is optionallysubstituted at the carbon attached to —NH— with alkyl (in oneembodimentmethyl) and ring containing nitrogen ring atom is optionallysubstituted at ring nitrogen with alkylcarbonyl (in one embodimentacetyl). Within the groups in Embodiment J, in one group of compounds R²is —CONH 1-methylcyclohex-1-yl.

Embodiment K

The compound of Formula (I) or salt thereof as defined in the Summary,embodiments A and B, and groups contained therein, wherein R² is —CONHR′where R′ is heterocyclylalkyl. Within the groups in Embodiment K, in onegroup of compounds R² is —CONHR′ where R′ is heterocyclylalkyl whereheterocyclyl ring is pyrrolidinyl, tetrahydropyranyl, piperidinyl,tetrahydrothiopyranyl, or 1,1,-dioxo-tetrahydrothiopyranyl. Within thegroups in Embodiment K, in another group of compounds R² is—COCH₂-heterocyclyl where heterocyclyl is 3-, or 4-pyrrolidinyl, 3- or4-tetrahydropyranyl, 3- or 4-piperidinyl, 3- or 4-tetrahydrothiopyranyl,or 3- or 4-1,1,-dioxo-tetrahydrothiopyranyl, each ring containingnitrogen ring atom is optionally substituted at ring nitrogen withalkylcarbonyl (in one embodiment acetyl) and each ring is optionallysubstituted at the carbon attached to —CH₂— with alkyl (in oneembodiment methyl).

Embodiment L

The compound of Formula (I) or salt thereof as defined in the Summary,embodiments A and B, and groups contained therein, wherein R² is —CONHR′where R′ is substituted alkyl. Within the groups in Embodiment L, in onegroup of compounds R² is —CONHR′ where R′ is alkyl substituted with oneor two hydroxyl, alkoxy, amino. Within the groups in Embodiment L, inanother group of compounds R² is —CONHR′ where R′ is1,3-dimethoxyprop-2-yl, —C(CH₃)₂CH₂NH₂, —CH(CH₃)CH₂OCH₃,1,3-dihydroxyprop-2-yl, —CH(CH₃)CH₂OH, 1,3-dihydroxy-2-methylprop-2-yl,—C(CH₃)(OC₂H₅)₂, —CH₂C(CH₃)₂CH₂OH, 2-hydroxypropyl, 3-methoxyprop-2-yl,2-methoxyprop-1-yl, 2,3-dihydroxyprop-1-yl, 2-methoxyethyl,3-methoxypropyl, —CH₂C(CH₃)₂OCH₃, 3-methoxybutyl, —C(CH₃)₂OCH₃, ormethoxymethyl.

Embodiment M

The compound of Formula (I) or salt thereof as defined in the Summary,embodiments A-L, and groups contained therein, wherein R⁵ is hydrogen,methyl, methoxy, fluoro, chloro, trifluoromethyl, cyano ortrifluoromethoxy. Within the groups in Embodiment M, in one group ofcompounds R⁵ is hydrogen.

Embodiment N

The compound of Formula (I) or salt thereof as defined in the Summary,embodiments A-M, and groups contained therein, wherein R⁴ is hydrogen,alkyl, alkoxy, hydroxyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl,hydroxyalkoxy, alkoxyalkyl, alkoxyalkyloxy, heterocyclylalkyl optionallysubstituted with one or two substitutents independently selected fromalkyl, halo, hydroxyalkyl, or alkoxyalkyl, heterocyclyloxy optionallysubstituted with one or two substitutents independently selected fromalkyl, halo, hydroxyalkyl, or alkoxyalkyl, heterocyclylalkyloxyoptionally substituted with one or two substitutents independentlyselected from alkyl, halo, hydroxyalkyl, or alkoxyalkyl, aminoalkyl, oraminoalkoxy.

(i) Within the groups in embodiment N, in one group of compounds R⁴ ishydrogen, alkyl, alkoxy, hydroxyl, halo, haloalkyl, or haloalkoxy.Within (i), in one group of compounds R⁴ is hydrogen, methyl, methoxy,fluoro, chloro, trifluoromethyl, cyano or trifluoromethoxy.

(ii) Within the groups in embodiment N, in one group of compounds R⁴ ishydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkyloxy,heterocyclylalkyl optionally substituted with one or two substitutentsindependently selected from alkyl, halo, hydroxyalkyl, or alkoxyalkyl,heterocyclyloxy optionally substituted with one or two substitutentsindependently selected from alkyl, halo, hydroxyalkyl, or alkoxyalkyl,heterocyclylalkyloxy optionally substituted with one or twosubstitutents independently selected from alkyl, halo, hydroxyalkyl, oralkoxyalkyl, aminoalkyl, or aminoalkoxy. Within (ii), in one group ofcompounds R⁴ is hydroxyalkoxy, alkoxyalkyloxy, heterocyclyloxyoptionally substituted with one or two substitutents independentlyselected from alkyl, halo, hydroxyalkyl, or alkoxyalkyl,heterocyclylalkyloxy optionally substituted with one or twosubstitutents independently selected from alkyl, halo, hydroxyalkyl, oralkoxyalkyl, or aminoalkoxy.

(iii) Within the groups in embodiment N, and subparts (i) and (ii), inone group of compounds R⁴ is attached to carbon meta to carbonsubstituted with R³ group.

Embodiment O

(i) The compound of Formula (I) or salt thereof as defined in theSummary, embodiments A-N, and groups contained therein, wherein n is 1.Within these groups of compounds, in one group of compounds alkylene ismethylene.

(ii) The compound of Formula (I) or salt thereof as defined in theSummary, embodiments A-N, and groups contained therein, wherein n is 0.

Embodiment P

The compound of Formula (I) or salt thereof as defined in the Summary,embodiments A-O, and groups contained therein, wherein Y is —NHCO—.

The compound of Formula (I) or salt thereof as defined in the Summary,embodiments A-O, and groups contained therein, wherein Y is —NHSO₂—.

The compound of Formula (I) or salt thereof as defined in the Summary,embodiments A-O, and groups contained therein, wherein Y is —CO—.

Embodiment Q

The compound of Formula (I) or salt thereof as defined in the Summary,embodiments A-P, and groups contained therein, wherein R^(c) ishydrogen.

The compound of Formula (I) or salt thereof as defined in the Summary,embodiments A-P, and groups contained therein, wherein R^(c) is methyl.

The compound of Formula (I) or salt thereof as defined in the Summary,embodiments A-P, and groups contained therein, wherein R^(c) isNH₂alkyl, alkylaminoalkyl, or dialkylaminoalkyl. In one embodiment,R^(c) is —CH₂NH₂, —CH₂NHCH₃, or —CH₂N(CH₃)₂

Compounds of the present disclosure can be made by the methods depictedin the reaction schemes shown below.

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as Aldrich ChemicalCo., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis,Mo.) or are prepared by methods known to those skilled in the artfollowing procedures set forth in references such as Fieser and Fieser'sReagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons,1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced OrganicChemistry, (John Wiley and Sons, 4th Edition) and Larock's ComprehensiveOrganic Transformations (VCH Publishers Inc., 1989). These schemes aremerely illustrative of some methods by which the compounds of thepresent disclosure can be synthesized, and various modifications tothese schemes can be made and will be suggested to one skilled in theart having referred to this disclosure. The starting materials and theintermediates, and the final products of the reaction may be isolatedand purified if desired using conventional techniques, including but notlimited to filtration, distillation, crystallization, chromatography andthe like. Such materials may be characterized using conventional means,including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure over a temperature range from about −78°C. to about 150° C., such as from about 0° C. to about 125° C., or suchas at about room (or ambient) temperature, e.g., about 20° C.

Compounds of this disclosure can be made by the methods depicted in thereaction schemes shown below.

Scheme 1 depicts the preparation of compounds of Formula (I) where R³ is—Y—CH═CHR^(c) or —Y—C(O)C≡CR^(d) and Y is —NR^(a)CO— or —NR^(a)SO₂ whereR^(a), R^(c), R^(d), R¹-R⁵ are as defined in the Summary.

Reaction of a compound of formula 1 where R is H or a nitrogenprotecting group such as SEM or TES, with a boronic acid compound offormula 2 where Ar, R^(a), R⁴ and R⁵ are as defined in the Summary,under Suzuki-Miyaura coupling reaction conditions provides a compound offormula 4. The reaction is carried out in the presence of a catalystsuch as Pd(PPh₃)₄ or PdCl(dppf)₂ and the like in a solvent mixture suchas dioxane and water or dimethoxyethane and water. Alternatively,compound 1 can be reacted under the Suzuki-Miyaura coupling with anitroaromatic boronic acid 3 and the nitro group subsequently reducedvia the action of Pd/C and hydrogen or with SnCl₂ in a solvent such asMeOH to afford compound 4. Compounds of formula 1, 2 and 3 are eithercommercially available or they can be prepared by methods well known inthe art. For example, a compound of formula 1, where X=Cl or Br, R=H ora PG such as SEM or TES and the like, R² is aminocarbonyl or acyl, andR¹ and Z¹ are defined in the Summary, can be prepared as shown inMethods (a), (b), or (c) below.

Method (a)

A compound of formula 1, where X=Cl or Br, R=H or a PG such as SEM orTES and the like, R² is aminocarbonyl and R¹ and Z¹ are defined in theSummary, can be prepared as shown in Methods (a), (b), or (c) below.

Formylation of a compound of formula 10 to give a compound of formula 11can be accomplished by heating 10 in hexamethylenetriamine intrifluoroacetic acid as described in US patent application publicationno. US2009/0215750A1. Compounds of formula 10 such as2-bromo-5H-pyrrolo[2,3-b]pyrazine and 5-bromo-1H-pyrrolo[2,3-b]pyridineare commercially available. A compound of formula 12 where R is anitrogen protecting group can be prepared by treating 11 with NaH in asolvent such as DMF followed by addition of SEMCl or other silylprotecting group such as TESC1. Treatment of compound 11 or 12 with asuitable oxidizing agent such as KH₂PO₄, NaClO₂ and sulfamic acid indioxane and water provides a 3-carboxy compound of formula 13 where R isH or nitrogen protecting group. Subsequent amide coupling with acommercially available amine of formula NHRR′ where R and R′ are groupsin the definition of aminocarbonyl using a suitable coupling reagentssuch as EDCI, DCC, and the like, and a base such as DMAP,diisopropylethylamine, and the like affords compounds of formula 1 whereX=Cl or Br, R=H or a PG such as SEM or TES and the like, and R² isaminocarbonyl and R′, and Z¹ are defined in the Summary.

A compound of formula 1, where X=Cl or Br, R=H or a PG such as SEM orTES and the like, R² is acyl, and R¹ and Z¹ are defined in the Summary,can be prepared as shown in Methods (b) or (c) below.

A compound of formula 10 can be treated with diethylaluminum chlorideand an acid chloride of formula RC(O)Cl where is a group in thedefinition of acyl in a solvent such as dichloromethane, and the like toafford a ketone of formula 1. Incorporation of the protecting group suchas SEM or TES can be accomplished as described in Method (a) to afford acompound of formula 1 where PG is protecting group.

Alternatively, a compound of formula 10 can be treated with KOH and analdehyde of formula RCHO where R is a group in the definition of acyl toafford a substituted alcohol of formula 14. Oxidation with, for example,Dess-Martin Periodinane in a solvent such as dichloromethane and thelike affords a compound of formula 1 where R is hydrogen which can beprotected as described in Method (a) to afford a compound of formula 1where PG is a nitrogen protecting group.

Compounds of formula 4 can be converted to compounds of Formula (I) asdescribed below. Compounds of Formula (I) where R³ is—NR^(a)CO—CH═CHR^(c) where R^(a) and R^(c) are as defined in the Summarycan be prepared by acylation compound 4 with an acid chloride such asacryloyl chloride of formula 5 in the presence of a base such astriethylamine. Compounds of Formula (I) where R³ is —Y—C(O)C≡CR^(d)where R^(a) and R^(d) are as defined in the Summary can be prepared byacylation compound 4 with a propynyl chloride of formula 7 in thepresence of a base such as triethylamine. Compounds of Formula (I) whereR³ is —NR^(a)CO—CH═CHR^(c) where R^(c) aminomethyl, alkylaminomethyl, ordialkylaminoalkyl and R^(c) are as defined in the Summary can beprepared by coupling 4 with an acid chloride of formula 6 under aminoacid coupling conditions to give a compound of formula 8 and furtherreaction with an amine of formula NHR′R′ where each R′ is independentlyhydrogen or alkyl. The nitrogen protected derivative of the compounds ofFormula (I) can then be converted to corresponding compounds of Formula(I) by removal of the nitrogen protecting group. When the nitrogenprotecting group is SEM or TES, it can be removed with an acid such astrifluoroacetic acid in a solvent such as dichloromethane followed bytreatment with NaOAc in EtOH.

Proceeding as described above but substituting acyl halide with sulfonylhalide provides compounds of Formula (I) where Y is —NR^(a)SO₂—.

Compounds of Formula (I) where R³ is -(alkylene)-Y—CH═CHR′ where Y is—NR^(a)CO— or —NR^(a)SO₂ where R^(a), R^(c), R^(d), and R′—R⁵ are asdefined in the Summary can be prepared as illustrated and described inScheme 2 below.

Compounds of Formula (I) where R³ is —(CH₂)—Y—CH≡CHR^(c) where Y is—NR^(a)CO— or —NR^(a)SO₂ where R^(a), R^(c), R^(d), and R′—R⁵ are asdefined in the Summary can be prepared by reacting a compound of formula1 with a compound of formula 15, followed by reduction of the cyanogroup with a suitable reducing agent such as Pd/C to give a compound offormula 16. Compound 16 is then converted to a compound of Formula (I)as described in Scheme 1 above.

Compounds of Formula (I) where R³ is -(alkylene)-Y—CH═CHR^(c) where Y is—NR^(a)CO— or —NR^(a)SO₂ where R^(a), R^(c), R^(d), and R′—R⁵ are asdefined in the Summary can be prepared by reacting a compound of formula1 with a boronic acid compound of formula 17 where PG is a suitablehydroxy protecting group to give a compound of formula 18. Removal ofthe hydroxyl protecting group followed by conversion of the resultinghydroxyl group to a suitable leaving group such as mesylate, tosylate,and the like provides a compound of formula 19. Compound 19 is thenconverted to a compound of formula 20 by treating 19 with an amine offormula NH₂R^(a) where R^(a) is as defined in the Summary. Compound 20is then converted to a compound of Formula (I) as described in Scheme 1above.

Compounds of formula 17 can be prepared in two steps from commerciallyavailable alcohols such as 2-(4-bromophenyl)ethanol,2-(3-bromophenyl)ethanol, 2-(6-bromopyridin-3-yl)ethanol,2-(5-bromopyridin-2-yl)ethanol, 4-bromobenzylalcohol,4-bromobenzylalcohol, 3-(3-bromophenyl)propan-1-ol,4-bromobenzenepropanol, 5-bromo-2-hydroxymethylpyridine,(2-Bromo-pyridin-5-yl)-methanol and the like. Protection of the alcoholmoiety as a TBS ether or other silyl protecting groups is accomplishedthrough methods well known in the art. Lithiation of the resulting arylhalide with a butyl lithium in a solvent such as THF followed byaddition of trimethylborate affords compound 17 (i.e PCT2007076431).

The JAK3 inhibitory activity of the compounds can be measured utilizingthe Biological assays 1-5 and 8 below. A determination of JAK3inhibitory activity by any of those assays is considered to be JAK3inhibitory activity within the scope of this disclosure even if any orall of the other assays do not result in a determination of kinaseinhibitory activity.

The compounds of the present disclosure can form an irreversiblecovalent bond to Cys 909 (UniprotKB Sequence ID P52333) of JAK3. Anirreversible covalent bond often imparts unique properties related tothe residence time of the compound within the cysteine-containingbinding site. In this context, residence time refers to the temporalduration of the compound-target complex under different conditions (see*Copeland R A, Pompliano D L, Meek T D. Drug-target residence time andits implications for lead optimization. Nat. Rev. Drug Discov. 5(9),730-739 (2006). The presence of a irreversible covalent bond can lead toan extended residence time when compared to a non-covalent compound.Residence time may be measured using an occupancy assay in a biochemicalor cellular environment. Additionally, residence time may be measuredusing a functional assay following a defined wash-out period. Theability of the compound of the disclosure to form irreversible covalentbond with Cys909 of JAK3 and the olefinic bond of-(alkylene)_(n)-Y—CH═CHR^(c) group in the compound of the disclosure,can be determined by the assays described in Biological Examples 6 and 7below. A determination of the binding irreversibility of the covalentbond between the cysteine residue and the olefinic bond of the compoundof the disclosure by any of Biological Examples 6-7 below is consideredto be binding irreversibility within the scope of this disclosure evenif one of the other methods does not result in a determination ofbinding irreversibility.

In general, the compounds of the present disclosure will be administeredin a therapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. Therapeuticallyeffective amounts of compounds of the present disclosure may range fromabout 0.01 to about 500 mg per kg patient body weight per day, which canbe administered in single or multiple doses. The dosage level can beabout 0.1 to about 250 mg/kg per day; about 0.5 to about 100 mg/kg perday. A suitable dosage level may be about 0.01 to about 250 mg/kg perday, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50mg/kg per day. Within this range the dosage can be about 0.05 to about0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day. For oraladministration, the compositions can be in the form of tabletscontaining about 1.0 to about 1000 milligrams of the active ingredient,particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250,300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the activeingredient. The actual amount of the compounds of the presentdisclosure, i.e., the active ingredient, will depend upon numerousfactors such as the severity of the disease to be treated, the age andrelative health of the subject, the potency of the compound beingutilized, the route and form of administration, and other factors.

In general, compounds of the present disclosure will be administered aspharmaceutical compositions by any one of the following routes: oral,systemic (e.g., transdermal, intranasal or by suppository), orparenteral (e.g., intramuscular, intravenous or subcutaneous)administration. The preferred manner of administration is oral using aconvenient daily dosage regimen, which can be adjusted according to thedegree of affliction. Compositions can take the form of tablets, pills,capsules, semisolids, powders, sustained release formulations,solutions, suspensions, elixirs, aerosols, or any other appropriatecompositions.

The choice of formulation depends on various factors such as the mode ofdrug administration (e.g., for oral administration, formulations in theform of tablets, pills or capsules including enteric coated or delayedrelease tablets or capsules are preferred) and the bioavailability ofthe drug substance. Recently, pharmaceutical formulations have beendeveloped especially for drugs that show poor bioavailability based uponthe principle that bioavailability can be increased by increasing thesurface area i.e., decreasing particle size. For example, U.S. Pat. No.4,107,288 describes a pharmaceutical formulation having particles in thesize range from 10 to 1,000 nm in which the active material is supportedon a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684describes the production of a pharmaceutical formulation in which thedrug substance is pulverized to nanoparticles (average particle size of400 nm) in the presence of a surface modifier and then dispersed in aliquid medium to give a pharmaceutical formulation that exhibitsremarkably high bioavailability.

The compositions are comprised of in general, a compound of the presentdisclosure in combination with at least one pharmaceutically acceptableexcipient. Such excipient may be any solid, liquid, semi-solid or, inthe case of an aerosol composition, gaseous excipient that is generallyavailable to one of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk and the like. Liquid and semisolid excipientsmay be selected from glycerol, propylene glycol, water, ethanol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesameoil, etc. Preferred liquid carriers, particularly for injectablesolutions, include water, saline, aqueous dextrose, and glycols.

Compressed gases may be used to disperse a compound of this disclosurein aerosol form. Inert gases suitable for this purpose are nitrogen,carbon dioxide, etc.

Other suitable pharmaceutical excipients and their formulations aredescribed in Remington's Pharmaceutical Sciences, edited by E. W. Martin(Mack Publishing Company, 20th ed., 2000).

The level of the compound in a formulation can vary within the fullrange employed by those skilled in the art. Typically, the formulationwill contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt% of a compound of formula (I) based on the total formulation, with thebalance being one or more suitable pharmaceutical excipients. Forexample, the compound is present at a level of about 1-80 wt %.

The compounds of the present disclosure may be used in combination withone or more other drugs in the treatment of diseases or conditions forwhich compounds of the present disclosure or the other drugs may haveutility, where the combination of the drugs together are safer or moreeffective than either drug alone. Such other drug(s) may beadministered, by a route and in an amount commonly used therefore,contemporaneously or sequentially with a compound of the presentdisclosure. When a compound of the present disclosure is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of the present disclosure is preferred. However, thecombination therapy may also include therapies in which the compound ofthe present disclosure and one or more other drugs are administered ondifferent overlapping schedules. It is also contemplated that when usedin combination with one or more other active ingredients, the compoundsof the present disclosure and the other active ingredients may be usedin lower doses than when each is used singly.

Accordingly, the pharmaceutical compositions of the present disclosurealso include those that contain one or more other active ingredients, inaddition to a compound of the present disclosure.

The above combinations include combinations of a compound of the presentdisclosure not only with one other active compound, but also with two ormore other active compounds. Likewise, compounds of the presentdisclosure may be used in combination with other drugs that are used inthe prevention, treatment, control, amelioration, or reduction of riskof the diseases or conditions for which compounds of the presentdisclosure are useful. Such other drugs may be administered, by a routeand in an amount commonly used therefore, contemporaneously orsequentially with a compound of the present disclosure. When a compoundof the present disclosure is used contemporaneously with one or moreother drugs, a pharmaceutical composition containing such other drugs inaddition to the compound of the present disclosure is preferred.Accordingly, the pharmaceutical compositions of the present disclosurealso include those that also contain one or more other activeingredients, in addition to a compound of the present disclosure. Theweight ratio of the compound of the present disclosure to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.

Where the patient in need is suffering from or at risk of suffering froman autoimmune disease, an inflammatory disease, or an allergy disease, acompound of the present disclosure can be used in with one or more ofthe following therapeutic agents in any combination: immunosuppressants(e.g., tacrolimus, cyclosporin, rapamicin, methotrexate,cyclophosphamide, azathioprine, mercaptopurine, mycophenolate, orFTY720), glucocorticoids (e.g., prednisone, cortisone acetate,prednisolone, methylprednisolone, dexamethasone, betamethasone,triamcinolone, beclometasone, fludrocortisone acetate,deoxycorticosterone acetate, aldosterone), non-steroidalanti-inflammatory drugs (e.g., salicylates, arylalkanoic acids,2-arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs, orsulphonanilides), Cox-2-specific inhibitors (e.g., valdecoxib,celecoxib, or rofecoxib), leflunomide, gold thioglucose, goldthiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline,TNF-.alpha. binding proteins (e.g., infliximab, etanercept, oradalimumab), abatacept, anakinra, interferon-.beta., interferon-.gamma.,interleukin-2, allergy vaccines, antihistamines, antileukotrienes,beta-agonists, theophylline, or anticholinergics.

Where the patient in need is suffering from or at risk of suffering froma proliferative disorder, the patient can be treated with a compound ofthe present disclosure in any combination with one or more otheranti-cancer agents. In some embodiments, one or more of the anti-canceragents are proapoptotic agents. Examples of anti-cancer agents include,but are not limited to, any of the following: gossyphol, genasense,polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin,tumor necrosis factor-related apoptosis-inducing ligand (TRAIL),5-aza-2′-deoxycytidine, all trans retinoic acid, doxorubicin,vincristine, etoposide, gemcitabine, imatinib (Gleevec™), geldanamycin,17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol,LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352,Taxol™, also referred to as “paclitaxel”, which is a well-knownanti-cancer drug which acts by enhancing and stabilizing microtubuleformation, and analogs of Taxol™, such as Taxotere™. Compounds that havethe basic taxane skeleton as a common structure feature, have also beenshown to have the ability to arrest cells in the G2-M phases due tostabilized microtubules and may be useful for treating cancer incombination with the compounds described herein.

Further examples of anti-cancer agents for use in combination with acompound of the present disclosure include inhibitors ofmitogen-activated protein kinase signaling, e.g., U0126, PD98059,PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006,wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies(e.g., rituxan).

Other anti-cancer agents that can be employed in combination with acompound of the present disclosure include Adriamycin, Dactinomycin,Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazolehydrochloride; acronine; adozelesin; aldesleukin; altretamine;ambomycin; ametantrone acetate; aminoglutethimide; amsacrine;anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa;azotomycin; batimastat; benzodepa; bicalutamide; bisantrenehydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate;brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone;caracemide; carbetimer; carboplatin; carmustine; carubicinhydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin;cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin;dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicinhydrochloride; droloxifene; droloxifene citrate; dromostanolonepropionate; duazomycin; edatrexate; eflornithine hydrochloride;elsamitrucin; enloplatin; enpromate; epipropidine; epirubicinhydrochloride; erbulozole; esorubicin hydrochloride; estramustine;estramustine phosphate sodium; etanidazole; etoposide; etoposidephosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide;floxuridine; fludarabine phosphate; fluorouracil; flurocitabine;fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride;hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine;interleukin II (including recombinant interleukin II, or rIL2),interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferonalfa-n3; interferon beta-1a; interferon gamma-1 b; iproplatin;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase;peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman;piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimersodium; porfiromycin; prednimustine; procarbazine hydrochloride;puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide;safingol; safingol hydrochloride; semustine; simtrazene; sparfosatesodium; sparsomycin; spirogermanium hydrochloride; spiromustine;spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin;tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin;teniposide; teroxirone; testolactone; thiamiprine; thioguanine;thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestoloneacetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate;triptorelin; tubulozole hydrochloride; uracil mustard; uredepa;vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate;vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicinhydrochloride.

Other anti-cancer agents that can be employed in combination with acompound of the present disclosure nclude: 20-epi-1, 25 dihydroxyvitaminD3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol;adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine;amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine;anagrelide; anastrozole; andrographolide; angiogenesis inhibitors;antagonist D; antagonist G; antarelix; anti-dorsalizing morphogeneticprotein-1; antiandrogen, prostatic carcinoma; antiestrogen;antineoplaston; antisense oligonucleotides; aphidicolin glycinate;apoptosis gene modulators; apoptosis regulators; apurinic acid;ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane;atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron;azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat;BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactamderivatives; beta-alethine; betaclamycin B; betulinic acid; bFGFinhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide;bistratene A; bizelesin; breflate; bropirimine; budotitane; buthioninesulfoximine; calcipotriol; calphostin C; camptothecin derivatives;canarypox IL-2; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron;doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen;ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur;epirubicin; epristeride; estramustine analogue; estrogen agonists;estrogen antagonists; etanidazole; etoposide phosphate; exemestane;fadrozole; fazarabine; fenretinide; filgrastim; fmasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorubicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone;oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronicacid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists;raltitrexed; ramosetron; ras famesyl protein transferase inhibitors; rasinhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186etidronate; rhizoxin; ribozymes; R.sub.11 retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B 1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived 1; sense oligonucleotides; signaltransduction inhibitors; signal transduction modulators; single chainantigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate;sodium phenylacetate; solverol; somatomedin binding protein; sonermin;sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin1; squalamine; stem cell inhibitor; stem-cell division inhibitors;stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactiveintestinal peptide antagonist; suradista; suramin; swainsonine;synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide;tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium;telomerase inhibitors; temoporfin; temozolomide; teniposide;tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietinreceptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyletiopurpurin; tirapazamine; titanocene bichloride; topsentin;toremifene; totipotent stem cell factor; translation inhibitors;tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin;tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBCinhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor;urokinase receptor antagonists; vapreotide; variolin B; vector system,erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin;vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin;zilascorb; and zinostatin stimalamer.

Yet other anticancer agents that can be employed in combination with acompound of the present disclosure include alkylating agents,antimetabolites, natural products, or hormones, e.g., nitrogen mustards(e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne,etc.), or triazenes (decarbazine, etc.). Examples of antimetabolitesinclude but are not limited to folic acid analog (e.g., methotrexate),or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g.,mercaptopurine, thioguanine, pentostatin).

Examples of natural products useful in combination with a compound ofthe present disclosure include but are not limited to vinca alkaloids(e.g., vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide),antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g.,L-asparaginase), or biological response modifiers (e.g., interferonalpha).

Examples of alkylating agents that can be employed in combination acompound of the present disclosure include, but are not limited to,nitrogen mustards (e.g., mechloroethamine, cyclophosphamide,chlorambucil, melphalan, etc.), ethylenimine and methylmelamines (e.g.,hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan),nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin,etc.), or triazenes (decarbazine, etc.). Examples of antimetabolitesinclude, but are not limited to folic acid analog (e.g., methotrexate),or pyrimidine analogs (e.g., fluorouracil, floxuridine, Cytarabine),purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.

Examples of hormones and antagonists useful in combination a compound ofthe present disclosure include, but are not limited to,adrenocorticosteroids (e.g., prednisone), progestins (e.g.,hydroxyprogesterone caproate, megestrol acetate, medroxyprogesteroneacetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol),antiestrogen (e.g., tamoxifen), androgens (e.g., testosteronepropionate, fluoxymesterone), antiandrogen (e.g., flutamide),gonadotropin releasing hormone analog (e.g., leuprolide). Other agentsthat can be used in the methods and compositions described herein forthe treatment or prevention of cancer include platinum coordinationcomplexes (e.g., cisplatin, carboblatin), anthracenedione (e.g.,mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazinederivative (e.g., procarbazine), adrenocortical suppressant (e.g.,mitotane, aminoglutethimide).

Examples of anti-cancer agents which act by arresting cells in the G2-Mphases due to stabilized microtubules and which can be used incombination with an irreversible Btk inhibitor compound include withoutlimitation the following marketed drugs and drugs in development:Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10and NSC-376128), Mivobulin isethionate (also known as CI-980),Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296),ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such asAltorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1,Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5,Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9),Cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356),Epothilones (such as Epothilone A, Epothilone B, Epothilone C (alsoknown as desoxyepothilone A or dEpoA), Epothilone D (also referred to asKOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F,Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B,21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D(also known as Desoxyepothilone F and dEpoF), 26-fluoroepothilone),Auristatin P E (also known as NSC-654663), Soblidotin (also known asTZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578(Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559(Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358(Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164(Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences),BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960(Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/KyowaHakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena),Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, alsoknown as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, also known asAVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide,Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969),T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1(Parker Hughes Institute, also known as DDE-261 and WHI-261), H10(Kansas State University), H16 (Kansas State University), Oncocidin A1(also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute),Fijianolide B. Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1(Parker Hughes Institute, also known as SPIKET-P), 3-IAABU(Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569),Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica),A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai Schoolof Medicine, also known as MF-191), TMPN (Arizona State University),Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine(also known as NSC-698666), 3-1AABE (Cytoskeleton/Mt. Sinai School ofMedicine), A-204197 (Abbott), T-607 (Tularik, also known as T-900607),RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin,Desaetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin),Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica),D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350(Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott),Diozostatin, (−)-Phenylahistin (also known as NSCL-96F037), D-68838(Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris,also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286(also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317(Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphatesodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411(Sanofi).

The following preparations of compounds of Formula (I) and intermediates(References) are given to enable those skilled in the art to moreclearly understand and to practice the present disclosure. They shouldnot be considered as limiting the scope of the disclosure, but merely asbeing illustrative and representative thereof.

Intermediate 1 Synthesis of 2-bromo-5H-pyrrolo[2,3-b]pyrazine

Step 1

A 500 ml three necked round bottom flask was charged with3,5-dibromopyrazine-2-amine (25.0 g, 0.0988 mole) which was dissolved inacetonitrile (250 ml). The reaction mixture was cooled to 0° C. andtriethylamine (50.0 g, 0.4941 mole), copper (1) iodide (2.26 g, 0.0119mole), and Pd (PPh₃)₄ (5.7 g, 0.0049 mole) were added under nitrogenatmosphere. The reaction mixture was stirred for 10 min at 0° C.followed by slow addition of trimethylsilylacetylene (10.7 g, 0.1089mole) over 15 min at the same temperature. After completion of theaddition, the reaction mixture was warmed up to RT and stirred for 90min. The reaction mixture was diluted by ethyl acetate and filtered. Thefiltrate was collected and washed with water. Layers were separated andaqueous layer was re-extracted by ethyl acetate. Combined organic layerwas dried over Na₂SO₄, filtered and concentrated to afford crude productwhich was purified using column purification to afford 20.0 g of5-bromo-3-((trimethylsilyl)ethynyl)pyrazine-2-amine. Step 2

To a 250 ml flask, potassium tert-butoxide (4.2 g, 0.037 mole) was addedfollowed by in THF (50 ml). To this,5-bromo-3-((trimethylsilyl)ethynyl)pyrazine-2-amine (10.0 g, 0.037 mole)in THF (50 ml) was added dropwise at RT over 20 min under nitrogenatmosphere. The mixture was stirred 30 min at same temperature and 60min at 65° C. The reaction mixture was cooled to RT and diluted withethyl acetate and filtered. The filtrate was collected and washed withwater. The layers were separated and the aq. layer was re-extracted withethyl acetate. The combined organic layer was dried over Na₂SO₄,filtered, and concentrated to afford crude product which was waspurified using column purification by eluting the compound with 15-20%ethyl acetate in hexanes to yield 4.3 g of2-bromo-5H-pyrrolo[2,3-b]pyrazine.

Intermediate 2 Synthesis of1-(2-(3-aminophenyl)-5H-pyrrolo[2,3-b]-pyrazin-7-yl)-2,2-dimethylpropan-1-one

Step 1

To a stirred solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (5 g, 25.25mmol) in 50 mL of dichloromethane at 0-5° C. was added diethyl aluminiumchloride (1.0 M in hexane, 76 mL, 75.75 mmol). The reaction mixture wasstirred at 0-5° C. for 30 min. Pivaloyl chloride (30.2 g, 252 mmol) wasadded to the reaction mixture and heated to reflux for 15 h. Saturatedaqueous NaHCO₃ (100 mL) solution was added carefully and extracted withethyl acetate. The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude product obtained waswashed with diethyl ether to get 4.5 g (63%) of1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethylpropan-1-one aslight yellow solid.

Step 2

To a stirred solution of1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethylpropan-1-one (600mg, 2.133 mmol) in 1,4-dioxane was added 3-aminophenyl boronic acid (348mg, 2.559 mmol), Pd(dppf)Cl₂ (519 mg, 0.633 mmol), potassium carbonate(879 mg, 6.39 mmol) under argon and heated to at 90° C. for 16 h. Aftercompletion of the reaction, the reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was separated andwashed with brine solution. The organic layer was dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude product waspurified by washing with diethyl ether to 190 mg (28%) of1-(2-(3-aminophenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethylpropan-1-oneas yellow oil.

Example 1 Synthesis ofN-(3-(7-pivaloyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)phenyl)acrylamide

To a stirred solution of1-(2-(3-aminophenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethylpropan-1-one(80 mg, 0.272 mmol) in N,N-dimethylacetamide was added acrylolylchloride (18 mg, 0.259 mmol) and stirred at 50° C. for 2 h. Aftercompletion of the reaction, the reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was separated andwashed with brine solution. The organic layer was dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude product waspurified by prep TLC over SiO₂ GF-254 using 40% ethyl acetate in petether as gradient to get 30 mg (32%) of(N-(3-(7-pivaloyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)phenyl)acrylamide asyellow solid. LC-MS: 98.07% (ES+APCI m/z: 349 (M+1).

Intermediate 3 Synthesis of2-(3-aminophenyl)-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

Step 1

To a reaction vial, 2-bromo-5H-pyrrolo[2,3-b]pyrazine (1 g, 5.05 mmol)was added in TFA (10 ml). Hexamine (1.06 g, 7.57 mmol) was added andreaction mixture was heated to 80° C. in, microwave for 15 min. Aftercompletion of the reaction, the reaction mixture was poured into aq.Na₂CO₃ solution. The solid obtained was filtered, dried and purifiedusing column purification by eluting with 3-5% EtOAc in Hexanes to yield0.450 g of 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde.

Step 2

To a 10 ml round bottom flask,2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (0.450 g, 1.99 mmol)and NaH (0.143 g, 5.97 mmol) were taken in DMF (5 ml) and stirred incooling for 15 min. SEM-Cl (0.497 g, 2.98 mmol) was added dropwise andstirred at rt for 2 h. After completion of the reaction, the reactionmixture was poured into water and extracted with ethyl acetate. Thecombined organics were washed with brine solution. The organic layer wasseparated and dried over sodium sulfate, concentrated to give the crudeproduct which was purified using column purification by eluting thecompound with 10% ethyl acetate in hexanes to yield 150 mg of2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde.

Step 3

To a 25 ml round bottom flask,2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde(0.1 g, 0.28 mmol) and sulfamic acid (0.163 g, 1.68 mmol) were taken indioxane (1 ml) and water (0.1 ml). A solution of NaClO₂ (0.032 g, 0.36mmol) and KH₂PO₄ (0.458 g, 3.36 mol) in water (0.9 ml) was added at 0°C. and the reaction mixture was stirred at room temperature for 2 h.After completion of the reaction, the reaction mixture was partitionedbetween water and ethyl acetate. The combined organics were washed withbrine solution. The organic layer was separated and dried over sodiumsulphate, concentrated to give 0.07 g of2-bromo-5-((2-(trimethylsilyl)ethoxy)-methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylicacid which was used as such in next step.

Step 3

To a 25 ml round bottom flask,2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylicacid (2.2 g, 0.00591 mol), EDC.HCl (1.35 g, 7.09 mol), HOBt (0.958 g,7.09 mmol), and DMAP (1.44 g, 0.0118 mol) were taken in DMF (20 ml) andstirred it for 15 min. tert-Butylamine (0.647 g, 8.87 mol) was addeddropwise and the reaction mixture was stirred at room temperatureovernight. After completion of the reaction, the reaction mixture waspoured into water and extracted with ethyl acetate. The combinedorganics were washed with brine solution. The organic layer wasseparated and dried over sodium sulphate, concentrated to give thedesired crude product which was purified using column purification byeluting the compound with 10% ethyl acetate in hexanes to yield 2.2 g of2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide.

Step 4

To a 35 ml microwave seal tube charged with2-bromo-N-isopropyl-5-((2-(trimethyl-silyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide(0.30 g, 0.70 mmole) and 3-nitrophenylboronic acid (0.13 g, 0.7 mmole)was added dioxane: water (8:2 ml). To the reaction mass was addedPdCl₂(dppf) (0.046 g, 0.05 mmole), K₂CO₃ (0.241 g, 0.00175 mole) and themixture degassed with N₂ gas for 15 min. The vial was sealed and heatedin a microwave reactor at 150° C. for 45 min. The reaction mixture wascooled to RT, diluted with ethyl acetate and water and filtered. Layersfrom filtrate were separated and the aqueous phase was re-extracted byethyl acetate. The combined organic layer was dried over Na₂SO₄,filtered and concentrated to afford crude product which was purified bychromatography.

The above process was repeated with additional 0.3 g and 0.4 g batchesand the crude mixtures combined before purification. The combinedmaterial was purified using column purification to yield 0.95 g ofN-tert-butyl-2-(3-nitrophenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]-pyrazine-7-carboxamide.

Step 5

In a 100 ml three necked round bottom flask,N-tert-butyl-2-(3-nitrophenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]-pyrazine-7-carboxamide(1.2 g, 2.5 mmole) was dissolved in methanol (35 ml). SnCl₂ (2.42 g,0.013 mole) was added in portions at 0° C. to 5° C. under nitrogenatmosphere. After 15 min at the same temperature, the mixture was heatedat reflux for 3 h. The reaction mixture was poured over saturatedaqueous NH₃ and water (20 ml+100 ml) and filtered. The filtrate wascollected, the layers were separated, and the aqueous phase was washedwith CH₂Cl₂. The combined organic layer was dried over Na₂SO₄, filteredand concentrated to yield 0.9 g of2-(3-aminophenyl)-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)-methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide.

Example 2 Synthesis of2-(3-acrylamidophenyl)-N-(tert-butyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

Step 1

In a 25 ml RBF,2-(3-aminophenyl)-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide(0.150 g, 0.34 mmole) was taken up in CH₂Cl₂ (4 ml) and cooled to −30°C. under N₂ atm. To this, acroloyl chloride (0.025 ml in CH₂Cl₂, 3.0mmole) was added dropwise to the reaction mass and stirred for 15 min.The mixture was made basic with saturated NaHCO₃ solution and extractedwith CH₂Cl₂. The organic layer was dried over Na₂SO₄ and concentrated.The product was taken up in THF (2 ml), DBU (0.2 ml) was added and thereaction mixture stirred at rt for 16 h. Water was added to the reactionmixture and product was extracted with CH₂Cl₂. The organic layer wasdried over Na₂SO₄ and evaporated to obtain a solid which was purified bytriturating with pentane to yield 0.150 g of2-(3-acryl-amidophenyl)-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide.

Step 2

To a 25 ml RBF,2-(3-acrylamidophenyl)-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)-methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide(0.1 g, 2 mmole) was taken up in CH₂Cl₂ (8 mL) and cooled to 0° C. underN2 atmosphere. TFA (2 ml) was added dropwise at 0° C. and stirred for 16h at rt. The solvent was evaporated under reduced pressure from thereaction mixture. To this, saturated NaHCO₃ solution was added dropwiseto make pH basic and the resultant precipitate was filtered out. Thesolid was washed with water and pentane and was then taken up in ethanol(20 ml) followed by addition of NaOAc.3H₂O (0.275 g, 2.0 mmole) toreaction mixture. After stirring 16 h, ethanol was evaporated underreduced pressure from the reaction mixture and the obtained solidmaterial was washed with water and pentane. The material was purified bytriturating with pentane to yield 0.029 g of2-(3-acrylamidophenyl)-N-tert-butyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide.LC-MS (ES, m/z): 364.2 [M+H].

Example 3 Synthesis ofN-(tert-butyl)-2-(3-(4-(dimethylamino)but-2-enamido)phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

Step 1

To a 25 ml three necked round bottom flask,2-(3-aminophenyl)-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide(0.3 g, 6.8 mmole) and 4-bromobut-2-enoic acid (0.13 g, 8.2 mmole) wastaken in CH₂Cl₂ (10 ml). The reaction mass was cooled to 0° C. and 50%T3P in ethyl acetate (0.43 g, 1.36 mmole) was added dropwise followed byDIPEA (0.35 g, 2.72 mmole) dropwise at the same temperature undernitrogen atmosphere. The reaction mass was stirred for 1 h at 0° C. andthen diluted with CH₂Cl₂ and water. The layers were separated and theaqueous layer was extracted by CH₂Cl₂. The combined organic layer wasdried over Na₂SO₄, filtered and concentrated to yield 0.35 g of2-3-(4-bromobut-2-enamido)phenyl)-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide.

Step 2

To a 10 ml single necked round bottom flask,2-(3-(4-bromobut-2-enamido)phenyl)-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide(0.2 g, 0.34 mmole) was taken in THF (3 ml). To this, dimethylamine (2Min THF) (0.016 g, 0.34 mmole) and TEA (0.087 g, 0.85 mole) was added atrt under N₂ atmosphere. The reaction mass was stirred for 3 h at 50° C.and then water was added to the reaction mixture and the aqueous layerwas extracted with ethyl acetate. The combined organic layer was driedover Na₂SO₄, filtered and concentrated to afford crude product. Thecrude compound was purified using column purification by eluting thecompound with 5-8% methanol in CH₂Cl₂ to yield 0.090 g ofN-tert-butyl-2-(3-(4-(dimethylamino)but-2-enamido)phenyl)-5-((2-(trimethylsilyl)ethoxy)-methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide.

Step 3

A 25 ml round bottom flask was charged withN-tert-butyl-2-(3-(4-(dimethylamino)but-2-enamido)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide(0.090 g, 0.1 mole) which was dissolved in CH₂Cl₂ (8 ml). To thisreaction mass TFA (2.0 ml) was added dropwise at 0° C. under N₂atmosphere and stirred at rt overnight. CH₂Cl₂ was distilled out and themixture made basic by addition of saturated NaHCO₃ solution added at 5°C. The aqueous layer was extracted using CH₂Cl₂. The organic layer wasdried over Na₂SO₄, filtered, and concentrated to afford the crudeproduct. This was taken up in ethanol (15 ml) and NaAc.3H2O (0.222 g,1.6 mmole) was added at RT. The reaction mass was stirred for 16 h atRT, diluted with ethyl acetate and the solvent removed under vacuum. Theresultant residual solid was washed with water and filtered, followed bytrituration with n-pentane. The solid was dried under vacuum to yield 45mg ofN-tert-butyl-2-(3-(4-(dimethylamino)but-2-enamido)phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide.LC-MS (ES, m/z): 421.3 [M+H].

Biological Examples Example 1 JAK3 Caliper Peptide Phosphorylation Assay

Phosphorylation of the appropriate peptide substrate (fluorescentlylabeled Srctide) by recombinant JAK3 (catalytic domain, aa 781-1124) wasmeasured in the presence and absence of different concentrations of testcompounds. Test compound, enzyme, fluorescently labeled substrate, andcofactors (ATP and Mg²⁺) were combined in a well of a microtiter plateand incubated for 2 hours at 25° C. The composition of the reactionbuffer was 100 mM HEPES pH 7.5, 5 mM MgCl₂, 0.01% Triton-X 100, 0.1%Bovine Serum Albumin, and 1% DMSO. Enzyme concentration in the finalreaction mixture was 0.5 nM while peptide substrate was at 1 uM. ATP wasused at 1×Km concentration corresponding to 2 uM. Serial dilutions(3-fold steps) of compounds were prepared in DMSO. At the end of theincubation, the reaction was stopped by the addition of 20 mM EDTA.Substrate and product (i.e. phosphorylated substrate) were separatedelectrophoretically and both were quantified by fluorescence intensityusing the microfluidics-based LabChip 3000 Drug Discovery System fromCaliper Life Sciences. Conversion for each well was calculated andplotted as function of test compound concentration. IC₅₀ value wasdetermined by fitting the data to a 4-parameter logistic model bynon-linear regression (XLfit model 205). In every assay, Staurosporinewas tested in the same manner as reference compound. Selectivity forJAK3 was determined using commercially available kinase cross-screeningservices (DiscoveRx, San Diego, Calif.).

The IC₅₀ of a representative number of compounds of the presentdisclosure is shown in Table below.

CPD # IC50 nm 1 0.0025 2 0.0005 3 0.0035

Example 2 JAK3 TR-FRET Assay

Inhibition of JAK3 enzymatic activity by compounds is measured usingtime-resolved fluorescence resonance energy transfer (TR-FRET). Here, asignal is observed only when a Europium-coupled phosphotyrosine antibodybinds the phosphorylated peptide. Test compounds are first prepared in100% DMSO and serially diluted 10 times via 3-fold dilution. 2.5 ul ofeach serial dilution of the test compound at 4-fold the final assayconcentration is next transferred to the 384-well assay plate (CorningCatalog #3676). A solution of 2-fold the final concentration of JAK3enzyme (Invitrogen Catalog # PV3855) and Alexafluor 647-coupled peptidesubstrate (Invitrogen Catalog #5693) is next prepared in advance in akinase buffer of 50 mM Hepes pH 7.5, 10 mM MgCl2, and 1 mM EGTA. Forthis solution, the final concentration of JAK3 and peptide is typically1 nM and 100 nM, respectively. 5 uL of this 2-fold mix of JAK3 andpeptide is added as the second step of the procedure to the 384-wellassay plate. To initiate the enzymatic reaction, 2.5 ul of a 4-foldexcess ATP solution in kinase buffer is added to the 384-well assayplate. Final ATP concentration is typically set to the Km for ATP. Thereaction is allowed to proceed for 60 minutes. During the kinasereaction, a stop solution consisting of EDTA and a Europium-containingphosphotyrosine antibody (Invtrogen Catalog #5692) is prepared inTR-FRET dilution buffer (Invitrogen Catalog #3574). The stop solutioncontains an EDTA concentration of 20 mM and an antibody concentration of4 nM. After the 60 minute, 10 ul of the stop solution is added to allwells. Each well is mixed and incubated for 30 minutes at roomtemperature. Plates are read on a Perkin Elmer Envision TR-FRET platereader under LanthaScreen settings. Excitation wavelength is 337 nm andEmission wavelengths are 620 nm and 665 nm. Data are acquired as theratio of emission at 665 nm/emission at 620 nm and plotted as a functionof compound concentration to ascertain compound potency. Selectivity forJAK3 will be determined using commercially available kinasecross-screening services (DiscoveRx, San Diego, Calif.).

Example 3 Cellular JAK3 Activity Measured by Stat6 Reporter Assay inRamos Cells

The beta lactamase-based select-screen reporter assay was used tomeasure JAK3 cell-based activity. The assay was preformed at Invitrogen.32 μL of STAT6-bla RA1 (Invitrogen) cells diluted in Assay Media(OPTI-MEM, 0.5% dialyzed FBS, 0.1 mM NEAA, 1 mM sodium pyruvate, 100U/ml/100 μg/ml Pen/Strep, 550 ng/ml CD40L) to 8×10⁶ cells/ml celldensity were added to the Poly-D-Lysine assay plate containing 4 μL of a10× serial dilution of a JAK3 control compound (JAK inhibitor I(Calbiochem)) or test compounds. Pre-incubation at 37° C./5% CO₂ in ahumidified incubator with test compound or control compound serialdilutions was for 30 minutes. 4 μL of 10× control activator IL-4 at thepredetermined EC80 concentration was added to wells containing thecontrol compound or test compound. The plate was incubated for 5 hoursat 37° C./5% CO₂ in a humidified incubator. 8 μL of 1 μM SubstrateLoading Solution consisting of Solution A (1 mM LiveBLAzer™-FRET B/GSubstrate); Solution B (Invitrogen), and Solution C (Invitrogen), wasadded to each well and the plate was incubated for 2 hours at roomtemperature. The plate was read on a fluorescence plate reader and thedata was analyzed. A response ratio was calculated from the emissions ofcleaved and uncleaved substrate. The response ratio of wells withcompound dilutions was compared with wells that contain only DMSO tocalculate the percent inhibition at each compound concentration. A doseresponse curve was constructed and an IC₅₀ was calculated.

Example 4 Blockade of Stat5 Phosphorylation in Whole Blood or PeripheralBlood Mononuclear Cell (PBMC)

Activation of the IL-2 receptor leads to increased JAK3 activity, Stat5phosphorylation and T cell activation (see O'Shea J. J, et. al. A newmodality for immunosuppression: targeting the JAK/STAT pathway. Nat RevDrug Discov. 3:555-64. 2004). JAK3 inhibitors have been shown to block Tcell activation as measured by Stat5 phosphorylation (see Lin et al.Selective functional inhibition of Jak-3 is sufficient for efficacy incollagen-induced arthritis in mice. Arthritis & Rheumatism 62:2283-2293.2010). Peripheral blood mononuclear cells (PBMC) were prepared fromhuman whole blood by centrifugation on a ficoll gradient. Aliquots ofPBMC were pre-incubated with serial dilutions of test compound for 30minutes followed by activation with IL-2 (pre-determined EC80concentration). Samples were incubated for 15 minutes and then fixedwith 2% paraformaldehyde for PBMCs. Fixed cells were stained withAlexa647-labeled anti-phosphoStat5 pY694 antibodies (BD Biosciences) for45 minutes. Stat5 phosphorylation was then analyzed by flow cytometry.The percent inhibition was calculated based on a DMSO control for noinhibition and plotted as a function of test compound concentration fromwhich an IC₅₀ value was calculated.

Example 5 Inhibition of Mouse Collagen-Induced Arthritis

Inhibition of murine collagen-induced arthritis (mCIA) is a standardanimal disease model for rheumatoid arthritis. Previous studies havedemonstrated that inhibition of JAK3 is efficacious in blocking mCIA(see Milici A. J, et al. Cartilage preservation by inhibition of Januskinase 3 in two rodent models of rheumatoid arthritis. Arthritis ResTher. 10:R14 1-9. 2008). Starting on day 0 DBA/1 mice are injected withan emulsion of Type II collagen in Complete Freund's Adjuvant. Mice areboosted 21 days later to synchronize development of disease. Afterdevelopment of mild disease, animals are enrolled in the study andrandomized. Dosing is oral, Q.D. typically for 11 days with testcompound or dexamethasone (0.2 mg/kg) as control. One group receivesvehicle alone. Clinical scoring (0-4) is based on the extent of swellingand severity of arthritis. Scores for all four paws are added formaximum score of 16. Anti-collagen antibodies and total Ig are measuredfor each animal by ELISA at the end of the study (Bolder BioPath,Boulder, Colo.).

Example 6 Determination of Drug-Kinase Residence Time for JAK3

The following is a protocol to distinguish whether a compound displays aslow or non-existent dissociation rate from JAK3, such as typicallywould occur if a covalent bond is formed between the compound and thetarget. The read-out for slow dissociation is the ability of thecompound of interest to block binding of a high affinity fluorescenttracer molecule to the kinase active site, as detected usingtime-resolved fluorescence resonance energy transfer (TR-FRET). Theexperiment was conducted in a buffer consisting of 50 mM Hepes pH 7.5,10 mM MgCl₂, 0.01% Triton X-100, and 1 mM EGTA.

The first step of the procedure was incubation of 500 nM JAK3(Invitrogen Cat. #PV3855) with 1.5 uM of a compound disclosed in Table 1for 30 minutes in a volume of 10 uL. The mixture was then diluted 5-foldby mixture of 10 uL JAK3/cmpd with 40 uL buffer. A 10 uL volume of thediluted kinase/compound solution was then added to a well of a smallvolume 384 well plate (such as Greiner Cat. #784076). In order to probefor reversibility of the kinase-compound binding interaction, acompetition solution containing both a high affinity fluorescent tracerand an antibody coupled to Europium was prepared. For JAK3, thecompetition solution contained 8 uM Tracer 236 (Invitrogen Cat.#PV5592), which is a proprietary high affinity ligand for JAK3 coupledto the fluorophore AlexaFluor 647. The competition solution alsocontained 80 nM of an Anti-GST antibody coupled to Europium which isdesigned to bind the GST purification tag in JAK3.

After addition of 10 uL of the competition solution to the Greinerplate, the mixture was incubated for one hour or greater to allow timefor dissociation of non-covalent inhibitors and binding of the highaffinity tracer. It was expected that covalent and slow dissociatinginhibitors will block binding of the tracer while rapidly dissociatingnon-covalent inhibitors will not. Binding of the tracer to JAK3 wasdetected using TR-FRET between the Europium moiety of the Anti-GSTantibody and the AlexaFluor 647 group of Tracer 236. Binding wasevaluated using a Perkin Elmer Envision instrument (Model 2101) equippedwith filters and mirrors compatible with LANCE-type TR-FRET experiments.Data were plotted at percentage of signal obtained in the absence ofcompetitor compound. The background signal was obtained by omission ofJAK3 from the reaction. For compound 1, compound 2, and compound 3, noincrease in binding of Tracer 236 was observed from 1 hour through 6hours of the experiment, consistent with irreversible engagement ofcompound to JAK3.

Example 7 Reversibility of Binding

The following approach was developed to differentiate compounds thatform irreversible bonds with their targets, such as acrylamidecompounds, from compound that bind reversibly. Reactions were preparedwith the JAK3 protein target at a higher concentration than the compoundof interest. The reactions were then digested with trypsin, disruptingproper folding of the target. It has been found that digestion withtrypsin returns reversible compounds to solution due to dissociationfrom the target while irreversible compounds remain bound to the target.The concentration of compound in solution was assessed both precedingand following perturbation using high performance liquid chromatography(HPLC) coupled to tandem mass spectrometry. Using this technique, it wasdemonstrated that an acrylamide-containing compound 1 (shown in tablebelow) was depleted from solution in both the native and perturbed state(See table below) and hence is an irreversible inhibitor.

Compound in solution in Compound in solution the denatured or digestedCpd in the native state? state? 1 no no

Example 8 Tumor Cell Proliferation Assay

Cells (SZ-4 CTCL cells) were plated at a density of 5000 cells/well (384well plates). Cells were plated in DMEM culture media supplemented with0.5% fetal bovine serum. Other tumor cells (e.g. NK-TCL, T-ALL) wereplated at densities of 2000-10,000 cells/well in culture media (e.g.DMEM, RPMI), containing 1%-20% FBS, dependent on the growth requirementsof the individual tumor cell line. Compounds were diluted in culturemedia using serial dilution yielding final concentrations with 0 (DMSOcontrol) or concentrations ranging from 0.5 nM to 10 uM. For the CTCLcells, after 1 hr incubation, at 37° C. in 95% air, 5% CO₂, cells wereinduced with 100 ng/ml IL-2 for 72 hr. For the other cell types, cellswere incubated without further induction for 72 hr. Cell Titer-Gloreagent was then added to the cells, contents mixed for 2 min, incubatedat room temperature for 10 min, then luminescence was determined using amicroplate luminometer. The percent inhibition was calculated based on aDMSO control for no inhibition and plotted as a function of testcompound concentration from which an IC₅₀ value was calculated.

Tumor Type and subtype if Cell Line known Cpd 2 IC₅₀ (μM) SZ-4 CTCL(Sézary syndrome) 0.056 Hut-102 CTCL (Mycosis fungoides) 0.104 H9 CTCL(Sézary syndrome) 0.450 H78 CTCL (Sézary syndrome) 0.150 HH CTCL (nonMF, non Sézary 2.700 syndrome) MJ CTCL (Unknown) >5.00 NKS1 NK-TCL 0.109KHG1 NK-TCL 0.498 SNK1 NK-TCL 0.735 SNK6 NK-TCL 8.42 HANK1 NK-TCL 1.87

Formulation Examples

The following are representative pharmaceutical formulations containinga compound of Formula (I).

Tablet Formulation

The following ingredients are mixed intimately and pressed into singlescored tablets.

Quantity per tablet Ingredient mg compound of this disclosure 400cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5

Capsule Formulation

The following ingredients are mixed intimately and loaded into ahard-shell gelatin capsule.

Quantity per capsule Ingredient mg compound of this disclosure 200lactose spray dried 148 magnesium stearate 2

Injectable Formulation

Compound of the disclosure (e.g., compound 1) in 2% HPMC, 1% Tween 80 inDI water, pH 2.2 with MSA, q.s. to at least 20 mg/ml

The foregoing disclosure has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Itwill be obvious to one of skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the disclosureshould, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to thefollowing appended claims, along with the full scope of equivalents towhich such claims are entitled.

What is claimed:
 1. A compound of Formula (I):

wherein: Z¹ is N or CR⁶ where R⁶ is hydrogen, alkyl, halo, haloalkyl,haloalkoxy, or cyano; R¹ is hydrogen, alkyl, halo, haloalkyl,haloalkoxy, cyano, or cycloalkyl; R² is hydrogen, alkyl, cycloalkyl,halo, cyano, acyl, aminocarbonyl, phenyl or heteroaryl wherein phenyland heteroaryl is optionally substituted with one, two or threesubstituents independently selected from alkyl, alkoxy, halo, haloalkyl,or haloalkoxy; Ar is phenyl, pyridinyl, pyridazinyl, pyrazinyl, orpyrimidinyl; R³ is -(alkylene)_(n)-Y—CH═CHR^(c) [where n is 0 or 1, Y is—NR^(a)CO—, —NR^(a)SO₂—, —CO— or —SO₂— (where R^(a) is hydrogen oralkyl) and R^(c) is hydrogen, alkyl, NH₂alkyl, alkylaminoalkyl, ordialkylaminoalkyl] and R³ is attached to carbon of the phenyl,pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl ring that is in metaposition to the carbon attaching the aforementioned rings to theazaindole core; R⁴ is hydrogen, alkyl, alkoxy, hydroxyl, halo,haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl,alkoxyalkyloxy, heterocyclylalkyl optionally substituted with one or twosubstitutents independently selected from alkyl, halo, hydroxyalkyl, oralkoxyalkyl, heterocyclyloxy optionally substituted with one or twosubstitutents independently selected from alkyl, halo, hydroxyalkyl, oralkoxyalkyl, heterocyclylalkyloxy optionally substituted with one or twosubstitutents independently selected from alkyl, halo, hydroxyalkyl, oralkoxyalkyl, aminoalkyl, or aminoalkoxy; and R⁵ is hydrogen, alkyl,alkoxy, hydroxyl, halo, haloalkyl, haloalkoxy, or cyano; or apharmaceutically acceptable salt thereof.
 2. The compound or apharmaceutically acceptable salt of claim 1 wherein the compound ofFormula (I) or salt thereof has the structure (Ib):


3. The compound or a pharmaceutically acceptable salt of claim 1 whereinAr is pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl, each ringsubstituted with R³ at the carbon atom that is in the meta position tothe carbon atom attaching the aforementioned rings to the azaindolecore.
 4. The compound or a pharmaceutically acceptable salt of any ofthe claims 1-3 wherein R² is hydrogen, alkyl, cycloalkyl, halo, cyano,—COR (where R is alkyl, heterocyclyl, heterocyclylalkyl or substitutedalkyl), or —CONR″R′ (where R″ is hydrogen or alkyl and R′ is hydrogen,alkyl, heterocyclyl, heterocyclylalkyl, or substituted alkyl).
 5. Thecompound or a pharmaceutically acceptable salt of any of the claims 1-3wherein R² is acyl.
 6. The compound or a pharmaceutically acceptablesalt of any of the claims 1-3 wherein R² is aminocarbonyl.
 7. Thecompound or a pharmaceutically acceptable salt of any of the claims 1-3wherein R² is —CONHR′ where R′ is isopropyl, isobutyl, or tert-butyl. 8.The compound or a pharmaceutically acceptable salt of any of the claims1-7 wherein R⁵ is hydrogen.
 9. The compound or a pharmaceuticallyacceptable salt of any of the claims 1-8 wherein R⁴ is hydrogen, alkyl,alkoxy, hydroxyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl,hydroxyalkoxy, alkoxyalkyl, alkoxyalkyloxy, heterocyclylalkyl optionallysubstituted with one or two substitutents independently selected fromalkyl, halo, hydroxyalkyl, or alkoxyalkyl, heterocyclyloxy optionallysubstituted with one or two substitutents independently selected fromalkyl, halo, hydroxyalkyl, or alkoxyalkyl, heterocyclylalkyloxyoptionally substituted with one or two substitutents independentlyselected from alkyl, halo, hydroxyalkyl, or alkoxyalkyl, aminoalkyl, oraminoalkoxy.
 10. The compound or a pharmaceutically acceptable salt ofclaim 9 wherein R⁴ is hydrogen, alkyl, alkoxy, hydroxyl, halo,haloalkyl, or haloalkoxy.
 11. The compound or a pharmaceuticallyacceptable salt of claim 9 wherein R⁴ is hydrogen, methyl, methoxy,fluoro, chloro, trifluoromethyl, cyano or trifluoromethoxy.
 12. Thecompound or a pharmaceutically acceptable salt of claim 9 wherein R⁴ ishydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkyloxy,heterocyclylalkyl optionally substituted with one or two substitutentsindependently selected from alkyl, halo, hydroxyalkyl, or alkoxyalkyl,heterocyclyloxy optionally substituted with one or two substitutentsindependently selected from alkyl, halo, hydroxyalkyl, or alkoxyalkyl,heterocyclylalkyloxy optionally substituted with one or twosubstitutents independently selected from alkyl, halo, hydroxyalkyl, oralkoxyalkyl, aminoalkyl, or aminoalkoxy.
 13. The compound or apharmaceutically acceptable salt of claim 9 wherein R⁴ is hydroxyalkoxy,alkoxyalkyloxy, heterocyclyloxy optionally substituted with one or twosubstitutents independently selected from alkyl, halo, hydroxyalkyl, oralkoxyalkyl, heterocyclylalkyloxy optionally substituted with one or twosubstitutents independently selected from alkyl, halo, hydroxyalkyl, oralkoxyalkyl, or aminoalkoxy.
 14. The compound or a pharmaceuticallyacceptable salt of claim 13 wherein R⁴ is attached to the carbon meta tothe carbon substituted with the R³ group.
 15. The compound or apharmaceutically acceptable salt of any of the claims 1-14 wherein nis
 1. 16. The compound or a pharmaceutically acceptable salt of claim 15wherein alkylene is methylene.
 17. The compound or a pharmaceuticallyacceptable salt of any of the claims 1-14 wherein n is
 0. 18. Thecompound or a pharmaceutically acceptable salt of any of the claims 1-17wherein Y is —NHCO—.
 19. The compound or a pharmaceutically acceptablesalt of any of the claims 1-18 wherein R^(c) is hydrogen.
 20. Thecompound or pharmaceutically acceptable salt of any of the claims 1-18wherein R^(c) is methyl.
 21. The compound or a pharmaceuticallyacceptable salt of any of the claims 1-18 wherein R^(c) is NH₂alkyl,alkylaminoalkyl, or dialkylaminoalkyl.
 22. A compound selected from:N-(3-(7-pivaloyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)phenyl)acrylamide;2-(3-acrylamidophenyl)-N-(tert-butyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide;N-(tert-butyl)-2-(3-(4-(dimethylamino)but-2-enamido)phenyl)-5H-pyrrolo[2,3-b]-pyrazine-7-carboxamide;an E or Z isomer thereof; and a pharmaceutically acceptable saltthereof.
 23. A pharmaceutical composition comprising a compound of anyof the claims 1-22, and/or a pharmaceutically acceptable salt thereof;and a pharmaceutically acceptable excipient.
 24. A method of treatingautoimmune disease, an inflammatory disease or cancer in a patient whichmethod comprises administering to the patient in need thereof, apharmaceutical composition comprising a therapeutically effective amounta compound of any of the claims 1-22 or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable excipient.
 25. Themethod of claim 24 wherein the cancer is CTCL or NK-T cell lymphoma. 26.The method of claim 24 or 25 wherein the compound is administeredoptionally in combination with one or more anticancer oranti-inflammatory agents.